The objectives are to investigate the pathogenesis of the bleeding diathesis in chronic renal failure (uremia) through studies on platelet function, primary hemostasis, and rheology in these patients. The specific aims are 1) to characterize more completely the nature and extent of the abnormalities of platelet function in platelets from uremic patients; 2) to examine in detail some of the biochemical pathways that are associated with platelet function as a means of probing the specific defects which may be responsible for the functional abnormalities. These studies will utilize techniques which have demonstrated, in patients with congenital platelet disorders, a variety of abnormalities in secretion-dependent and secretion-independent mechanisms and, in some cases, abnormalities in arachidonate and phospholipid metabolism; 3) to examine whether a defect in platelet interaction with subendothelium exists, utilizing an experimental model (for exposing subendothelium to anticoagulated blood under controlled shear conditions) which has been utilized to demonstrate abnormalities of platelet adhesion/thrombus formation in von Willebrand's disease and congenital platelet disorders, and to determine the basis for such a defect; 4) to study the mechanisms which may account for the findings in recent studies demonstrating a shortening of the bleeding time in uremic patients after transfusion of packed red cells by focusing on the question whether this effect is primarily due to physical properties of red cells in enhancing the diffusivity of platelets, or whether other possible effects of red cells in promoting hemostasis may also be involved; 5) to explore possible defects in the coagulation mechanism by studying platelet-vessel interaction, fibrin deposition, and fibrinopeptide A (FPA) production after exposure of subendothelium to directly sampled (non-anticoagulated) venous blood; 6) to utilize a recently developed technique for analyzing the primary arrest of bleeding through measurements of thromboxane B2 (TxB2), platelet factor 4 (PF4), FPA, and 6-keto-PGF-1Alpha in sequential samples of incisional blood obtained during performance of the bleeding time and, through these studies, to ascertain whether abnormalities of platelet function, prostacyclin (PGI2), arachidonate metabolism, and coagulation in uremia may be detected in vivo; 7) to study the effect of DDAVP on platelet adhesion and the role of large von Willebrand multimers during primary hemostasis.